Abstract
Social processes are associated with depression, particularly understanding and responding to others, deficits in which can manifest as callousness/unemotionality (CU). Thus, CU may reflect some of the genetic risk to depression. Further, this vulnerability likely reflects the neurological substrates of depression, presenting biomarkers to capture genetic vulnerability of depression severity. However, heritability varies within brain regions, so a high-resolution genetic perspective is needed. We developed a toolbox that maps genetic and environmental associations between brain and behavior at high resolution. We used this toolbox to estimate brain areas that are genetically associated with both depressive symptoms and CU in a sample of 258 same-sex twin pairs from the Colorado Longitudinal Twin Study (LTS). We then overlapped the two maps to generate coordinates that allow for tests of downstream effects of genes influencing our clusters. Genetic variance influencing cortical thickness in the right dorsal lateral prefrontal cortex (DLFPC) sulci and gyri, ventral posterior cingulate cortex (PCC), pre-somatic motor cortex (PreSMA), medial precuneus, left occipital-temporal junction (OTJ), parietal–temporal junction (PTJ), ventral somatosensory cortex (vSMA), and medial and lateral precuneus were genetically associated with both depression and CU. Split-half replication found support for both DLPFC clusters. Meta-analytic term search identified “theory of mind”, “inhibit”, and “pain” as likely functions. Gene and transcript mapping/enrichment analyses implicated calcium channels. CU reflects genetic vulnerability to depression that likely involves executive and social functioning in a distributed process across the cortex. This approach works to unify neuroimaging, neuroinformatics, and genetics to discover pathways to psychiatric vulnerability.
Highlights
As depression follows a normal distribution of risk across the population[1], relating depression to psychological features will better define pathways for addressing disorder vulnerability[2]
The total scanning session lasted 1 h 25 min; the current analyses focus on gray matter structure, obtained with a highresolution T1-weighted Magnetization Prepared Gradient Echo sequence in 224 sagittal slices, with a repetition time (TR) = 2400 ms, echo time (TE) = 2.01 ms, flip angle = 8°, field of view (FoV) = 256 mm, and voxel size of 0.8 mm[3]
Transcripts, cell types, and functions associated with our genetic clusters Using Montreal Neurological Institute coordinates (MNI) coordinates, we examined the overlap of our clusters with other sources of data: (1) the Allen brain atlas transcriptomic atlas and genome-wide association study (GWAS) results from the Psychiatric Genomics Consortium depression mega-analyses of 480,359 individuals[1], (2) Neurosynth meta-analytical database of functional activation across over 10,000 fMRI studies[19], and the (3) Yeo 7-network parcellation[36]
Summary
As depression follows a normal distribution of risk across the population[1], relating depression to psychological features will better define pathways for addressing disorder vulnerability[2]. Disruption in the ability to process social cues is associated with depressive symptomology, and can lead to increased deficits in daily functioning in both patient and subclinical groups[3]. Depressed individuals’ symptoms relate to specific facets of social behavior, namely, reasoning through others emotions[4,5,6], fitting under the “understanding mental states” subcategory of the “social dimensions” construct in the US National Institute of Mental Health Research. Many forms of social response have been associated with depression[7], and it is thought that broad deficits in social functioning may be influential in categories of severe depression. Social deficits in theory of mind, the ability to understand others’ thoughts, are related to poor mentalizing/metacognition, or inability to understand the self. Theory of mind predicts depression diagnosis above and beyond metacognition in behavioral studies[8]
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